Treatment of oppositional defiant disorder

ABSTRACT

Norepinephrine reuptake inhibitors are used to treat oppositional defiant disorder.

PRIORITY INFORMATION

This application claims the benefit of priority of U.S. ProvisionalPatent Application 60/059,629 filed Sep. 23, 1997.

FIELD OF THE INVENTION

The invention belongs to the fields of pharmaceutical chemistry andpsychiatric medicine, and provides a method of treatment of thepsychiatric disorder known as oppositional defiant disorder.

BACKGROUND OF THE INVENTION

Children and adolescents suffering from oppositional defiant disorderexhibit a pattern of hostile, defiant, and negative behavior more oftenthan is commonly observed in other individuals of the same mental age.They are argumentative with adults, are often angry and resentful,frequently lose their temper, swear, defy rules and requests fromadults, and deliberately engage in annoying behavior. They also tend tonot see themselves as a problem, but rather justify their behavior as aresponse to unreasonable circumstances.

Oppositional defiant disorder (ODD) is many times treated with the sametherapies employed for the treatment of Attention-deficit HyperactivityDisorder (ADHD), e.g., methylphenidate (Ritalin™), which exhibitsnoradrenergic and dopaminergic effects. Gross has demonstrated thatcertain ODD symptoms may be ameliorated by augmentation of standard ADHDtherapies with buspirone in certain patients (Gross, J. Am. Acad. ChildAdolesc. Psychiatry, 34(10), 1260 (1995)). Many patients are refractoryto these treatments, or discontinue treatment due to intolerable sideeffects. Furthermore, due to the high potential for substance abuse inoppositional defiant disorder patients, the use of stimulants such asmethylphenidate is problematic.

The need for a safe and effective treatment for oppositional defiantdisorder, without the disadvantages of current therapies, continues tobe a concern of the psychiatric community.

SUMMARY OF THE INVENTION

The present invention provides a method of treating oppositional defiantdisorder comprising the administration to a patient in need of suchtreatment of an effective amount of a norepinephrine reuptake inhibitor.

DETAILED DESCRIPTION

Many compounds, including those discussed at length below, arenorepinephrine reuptake inhibitors, and no doubt many more will beidentified in the future. In the practice of the present invention, itis intended to include reuptake inhibitors which show 50% effectiveconcentrations of about 1000 nM or less, in the protocol described byWong et al., Drug Development Research, 6, 397 (1985). Thenorepinephrine reuptake inhibitors useful for the method of the presentinvention are characterized in being selective for the inhibition ofneurotransmitter reuptake relative to their ability to act as directagonists or antagonists at other receptors. Norepinephrine reuptakeinhibitors useful for the method of the present invention include, butare not limited to:

Tomoxetine, (R)-(-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, isusually administered as the hydrochloride salt. Tomoxetine was firstdisclosed in U.S. Pat. No. 4,314,081. The word "tomoxetine" will be usedhere to refer to any acid addition salt or the free base of themolecule. See, for example, Gehlert, et al., Neuroscience Letters, 157,203-206 (1993), for a discussion of tomoxetine's activity as anorepinephrine reuptake inhibitor;

The compounds of formula I: ##STR1## wherein X is C₁ -C₄ alkylthio, andY is C₁ -C₂ alkyl or a pharmaceutically acceptable salt thereof. Thecompounds of formula I were described in U.S. Pat. No. 5,281,624, ofGehlert, Robertson, and Wong, and in Gehlert, et al., Life Sciences,55(22), 1915-1920, (1995). The compounds are there taught to beinhibitors of norepinephrine reuptake in the brain. It is also explainedthat the compounds exist as stereoisomers, and that they accordinglyinclude not only the racemates, but also the isolated individual isomersas well as mixtures of the individual isomers. For example, thecompounds of formula I include the following exemplary species:

N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propylamine benzoate;

(R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)propylamine hydrochloride;

(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propylamine;

N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propylamine malonate;

(S)-N-methyl-3-phenyl-3-(2-tert-butylthiophenoxy)propylaminenaphthalene-2-sulfonate;

(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine;

Reboxetine (Edronax™), 2-[α-(2-ethoxy)phenoxybenzyl]morpholine, isusually administered as the racemate. It was first taught by U.S. Pat.No. 4,229,449, which describes its utility for the treatment ofdepression. Reboxetine is a selective norepinephrine reuptake inhibitor.The term "reboxetine" will be used here to refer to any acid additionsalt or the free base of the molecule existing as the racemate or eitherenantiomer;

Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, isusually administered as the hydrochloride salt and as the (+)enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which showsits high potency. The word "duloxetine" will be used here to refer toany acid addition salt or the free base of the molecule;

Venlafaxine is known in the literature, and its method of synthesis andits activity as an inhibitor of serotonin and norepinephrine uptake aretaught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compoundA in that patent; and

Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide)is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as itsExample 4. The patent describes its compounds as antidepressants. Moretet al., Neuropharmacology 24, 1211-19 (1985), describe itspharmacological activities as an inhibitor of serotonin andnorepinephrine reuptake.

All of the U.S. patents which have been mentioned above in connectionwith compounds used in the present invention are incorporated herein byreference.

A preferred duloxetine enteric formulation is a pellet formulationcomprising a) a core consisting of duloxetine and a pharmaceuticallyacceptable excipient; b) an optional separating layer; c) an entericlayer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS)and a pharmaceutically acceptable excipient; d) an optional finishinglayer. The following example demonstrates the preparation of a preferredsuch formulation.

EXAMPLE 10 mg Duloxetine Base/Capsule

    ______________________________________                                        Bill of Materials                                                             ______________________________________                                        Beads                                                                           Sucrose - starch nonpareils, 60.28 mg                                         20-25 mesh                                                                    Duloxetine layer                                                              Duloxetine 11.21                                                              Hydroxypropylmethylcellulose 3.74                                             Separating layer                                                              Hydroxypropylmethylcellulose 2.51                                             Sucrose 5.00                                                                  Talc, 500 mesh 10.03                                                          Enteric layer                                                                 HPMCAS, LF grade, Shin-Etsu Chemical 25.02                                    Co., Tokyo, Japan                                                             Triethyl citrate 5.00                                                         Talc, 500 mesh 7.52                                                           Finishing layer                                                               Hydroxypropylmethylcellulose 8.44                                             Titanium dioxide 2.81                                                       Talc                  Trace                                                                         154.60     mg                                           ______________________________________                                    

The duloxetine layer was built up by suspending duloxetine in a 4% w/wsolution of the hydroxypropylmethyl-cellulose in water, and milling thesuspension with a CoBall Mill (Fryma Mashinen A G, Rheinfelden,Switzerland) model MS-12. A fluid bed dryer with a Wurster column wasused to make this product, at a batch size of 1.0 kg. The separatinglayer was added from a 4% w/w solution of thehydroxypropyl-methylcellulose in water, in which the sucrose was alsodissolved.

In order to prepare the enteric coating suspension, purified water wascooled to 10° C. and the polysorbate, triethyl citrate and siliconeemulsion were added and dispersed or dissolved. Then the HPMCAS and talcwere added and agitated until homogeneity was obtained, and the HPMCASwas fully neutralized by addition of ammonium hydroxide until solutionof the polymer was complete. To this suspension, acarboxymethylcellulose aqueous solution, 0.5% w/w, was added and blendedthoroughly. The enteric suspension was maintained at 20° C. during thecoating process. The enteric suspension was then added to the partiallycompleted pellets in the Wurster column at a spray rate of about 15ml/min, holding the temperature of the inlet air at about 50° C. Theproduct was dried in the Wurster at 50° C. when the enteric suspensionhad been fully added, and then dried on trays for 3 hours in a dry houseat 60° C. A finishing layer was then applied which consisted of a 4.5%w/w/hydroxypropylmethyl-cellulose solution containing titanium dioxideand propylene glycol as plasticizer. The pellets were completely driedin the fluid bed dryer and then were then filled in size 3 gelatincapsules.

While all compounds exhibiting norepinephrine reuptake inhibition areuseful for the method of the present invention, certain are preferred.It is preferred that the norepinephrine reuptake inhibitor is selectivefor norepinephrine over other neurotransmitters. It is also preferredthat the norepinephrine reuptake inhibitor is selected from tomoxetine,reboxetine, or a compound of formula I. It is especially preferred thatthe norepinephrine reuptake inhibitor be selected from tomoxetine,reboxetine, or (R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine.

It will be understood by the skilled reader that most or all of thecompounds used in the present invention are capable of forming salts,and that the salt forms of pharmaceuticals are commonly used, oftenbecause they are more readily crystallized and purified than are thefree bases. In all cases, the use of the pharmaceuticals described aboveas salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them.

Many of the compounds used in this invention are amines, and accordinglyreact with any of a number of inorganic and organic acids to formpharmaceutically acceptable acid addition salts. Since some of the freeamines of the compounds of this invention are typically oils at roomtemperature, it is preferable to convert the free amines to theirpharmaceutically acceptable acid addition salts for ease of handling andadministration, since the latter are routinely solid at roomtemperature. Acids commonly employed to form such salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids, such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, b-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid.

Administration

The dosages of the drugs used in the present invention must, in thefinal analysis, be set by the physician in charge of the case, usingknowledge of the drugs, the properties of the drugs in combination asdetermined in clinical trials, and the characteristics of the patient,including diseases other than that for which the physician is treatingthe patient. General outlines of the dosages, and some preferreddosages, can and will be provided here.

Tomoxetine: from about 5 mg/day to about 100 mg/day; preferably in therange from about 5 to about 70 mg/day; more preferably from about 10 toabout 60 mg/day; and still more preferably from about 10 to about 50mg/day;

Compounds of formula I: from about 0.01 mg/kg to about 20 mg/kg;preferred daily doses will be from about 0.05 mg/kg to 10 mg/kg; ideallyfrom about 0.1 mg/kg to about 5 mg/kg;

Reboxetine: from about 1 to about 30 mg, once to four times/day;preferred, from about 5 to about 30 mg once/day;

Duloxetine: from about 1 to about 30 mg once/day; preferred, from about5 to about 20 mg once/day;

Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred,from about 25 to about 125 mg thrice/day; and

Milnacipran: from about 10 to about 100 mg once-twice/day; preferred,from about 25 to about 50 mg twice/day.

All of the compounds concerned are orally available and are normallyadministered orally, and so oral administration is preferred. However,oral administration is not the only route or even the only preferredroute. For example, transdermal administration may be very desirable forpatients who are forgetful or petulant about taking oral medicine. Thedrugs may also be administered by the percutaneous, intravenous,intramuscular, intranasal or intrarectal route, in particularcircumstances. The route of administration may be varied in any way,limited by the physical properties of the drugs and the convenience ofthe patient and the caregiver.

The best description of oppositional defiant disorder is the diagnosticcriteria published by the American Psychiatric Association in theDSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, ThirdEdition-Revised (1987)), as follows.

Diagnostic Criteria for Oppositional Defiant Disorder

A. A disturbance of at least six months, during which at least five ofthe following are present:

(1) often loses temper

(2) often argues with adults

(3) often actively defies of refuses adult requests or rules, e.g.,refuses to do chores at home

(4) often deliberately does things that annoy other people, e.g., grabsother children's hats

(5) often blames others for his or her own mistake

(6) is often touchy or easily annoyed by others

(7) is often angry and resentful

(8) is often spiteful or vindictive

(9) often swears or uses obscene language

B. Does not meet the criteria for Conduct Disorder, and does not occurexclusively during the course of a psychotic disorder, Dysthymia, or aMajor Depressive, Hypomanic, or Manic Episode.

Patients suffering from Oppositional Defiant Disorder also commonlysuffer concomitantly from Attention-deficit Hyperactivity Disorder. Thepatient will benefit from the use of norepinephrine reuptake inhibitorsin the amelioration of the symptoms of Oppositional Defiant Disorderregardless of this or other co-morbid conditions. Furthermore, a patientsuffering from Oppositional Defiant Disorder and Attention-deficitHyperactivity Disorder will receive benefit in the amelioration ofsymptoms of both conditions through the method of the present invention.

The method of the present invention is effective in the treatment ofpatients who are children or adolescents, and there is no significantdifference in the symptoms or the details of the manner of treatmentamong patients of different ages. In general terms, however, forpurposes of the present invention, a child is considered to be a patientbelow the age of puberty, and an adolescent is considered to be apatient from the age of puberty up to about 18 years of age.

Inhibition or Norepinephrine Reuptake

The ability of compounds to inhibit the reuptake of norepinephrine maybe measured by the general procedure of Wong, et al., supra.

Male Sprague-Dawley rats weighing 150-250 gm are decapitated and brainsare immediately removed. Cerebral cortices are homogenized in 9 volumesof a medium containing 0.32 M sucrose and 10 mM glucose. Crudesynaptosomal preparations are isolated after differential centrifugationat 1000×g for 10 minutes and 17,000×g for 28 minutes. The final pelletsare suspended in the same medium and kept in ice until use within thesame day.

Synaptosomal uptake of ³ H-norepinephrine is determined as follows.Cortical synaptosomes (equivalent to 1 mg of protein) are incubated at37° C. for 5 minutes in 1 mL Krebs-bicarbonate medium containing also 10mM glucose, 0.1 mM iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50nM ³ H-norepinephrine. The reaction mixture is immediately diluted with2 mL of ice-chilled Krebs-bicarbonate buffer and filtered under vacuumwith a cell harvester (Brandel, Gaithersburg, Md.). Filters are rinsedtwice with approximately 5 mL of ice-chilled 0.9% saline and the uptakeof ³ H-norepinephrine assessed by liquid scintillation counting.Accumulation of ³ H-norepinephrine at 4° C. is considered to bebackground and is subtracted from all measurements. The concentration ofthe test compound required to inhibit 50% of the ³ H-norepinephrineaccumulation (IC₅₀ values) are determined by linear regression analysis.

We claim:
 1. A method of treating oppositional defiant disordercomprising administration to a patient in need of such treatment aneffective amount of a norepinephrine reuptake inhibitor selective fornorepinephrine over other neurotransmitters.
 2. A method of claim 1wherein the norepinephrine reuptake inhibitor is selected from the groupconsisting of tomoxetine, reboxetine and a compound of formula I:##STR2## wherein X is C₁ -C₄ alkylthio, and Y is C₁ -C₂ alkyl or apharmaceutically acceptable salt thereof.
 3. A method of claim 2 whereinthe norepinephrine reuptake inhibitor is tomoxetine.
 4. A method ofclaim 2 wherein the norepinephrine reuptake inhibitor is tomoxetinehydrochloride.
 5. A method of claim 2 wherein the norepinephrinereuptake inhibitor is reboxetine.
 6. A method of claim 2 wherein thenorepinephrine reuptake inhibitor is(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine.